Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From the MAVA-LTE Study, EXPLORER-LTE Cohort.

This study was funded by Bristol Myers Squibb, Princeton, New Jersey, USA. Bristol Myers Squibb’s policy on data sharing is available online at https://www.bms.com/researchers-and-partners/clinicaltrials-and-research/disclosure-commitment.html. Dr Rader has received consulting fees from Medtronic, Bristol Myers Squibb, and ReCor Medical. Dr Ore˛ziak has received personal fees from Bristol Myers Squibb. Dr Saberi has received personal fees from Bristol Myers Squibb. Dr Fermin has received consulting fees from Alnylam, Eidos Therapeutics, Bristol Myers Squibb, and Pfizer. Dr Wheeler has received personal fees and research support from Bristol Myers Squibb. Dr Garcia-Pavia has received consulting and speaking fees from Bristol Myers Squibb, Rocket Pharmaceuticals, and Cytokinetics and speaking fees from Bristol Myers Squibb and Cytokinetics. Dr Zwas has received personal fees from Bristol Myers Squibb. Dr Masri has received grants from Akcea, Pfizer, and Ultromics and consulting fees from Alnylam, Cytokinetics, Eidos Therapeutics, Ionis, and Pfizer. Dr Owens has received consulting fees from Bristol Myers Squibb, Cytokinetics, and Pfizer. Dr Hegde serves on the faculty of the Cardiovascular Imaging Core Laboratory at Brigham and Women’s Hospital, and her institution has received payments for her consulting work from Bristol Myers Squibb. Dr Seidler has received consulting fees or honoraria for lectures from Bristol Myers Squibb and Cytokinetics. Dr Balaratnam and Dr Sehnert are employees of Bristol Myers Squibb and own stock of Bristol Myers Squibb. Shawna Fox is an employee of IQVIA, a partner providing statistics services to Bristol Myers Squibb. Dr Olivotto has received grants from Amicus, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Genzyme, and Menarini International and consulting fees from Amicus, Cytokinetics, Genzyme, MS Pharma, Rocket Pharmaceuticals, and Tenaya Therapeutics.BACKGROUND Data assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed. OBJECTIVES The authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655). METHODS After mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms. RESULTS Between April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: -35.6 ± 32.6 mm Hg; Valsalva: -45.3 ± 35.9 mm Hg), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (median: -480 ng/L; Q1-Q3: -1,104 to -179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events. CONCLUSIONS Mavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up.S

Treatment of Heart Failure Patients with Anxiolytics Is Associated with Adverse Outcomes, with and without Depression

Background: Few studies have evaluated the effect of pharmacologic treatment of anxiety on outcomes in heart failure (HF) patients. This study examined the impact of treatment with anxiolytics on clinical outcomes in a real-world sample of HF patients with and without depression. Methods: Patients diagnosed with HF were retrieved from a large HMO database. Patients prescribed anxiolytic medication and patients diagnosed with depression and/or prescribed anti-depressant medication were followed for cardiac-related hospitalizations and death. Results: The study cohort included 6293 HF patients. Treatment with anxiolytics was associated with decreased one-year survival compared to untreated individuals, with a greater reduction in survival seen in patients diagnosed with depression and/or treated with anti-depressants. Multi-variable analysis adjusting for age, sex, NYHA class, cardiac risk factors and laboratory parameters found that treatment with anxiolytics remained a predictor of mortality even when adjusting for depression. Depression combined with anxiolytic treatment was predictive of increased mortality, and treatment with anxiolytics alone, depression alone and anxiolytic treatment together with depression were each associated with an increased hazard ratio for a composite outcome of death and hospitalization. Conclusions: In this real-world study of HF patients, both treatment with anxiolytics and depression were associated with increased mortality, and anxiolytic therapy remained a predictor of mortality when adjusting for depression. Treatment of anxiety together with depression was associated with the highest risk of mortality. Safe and effective treatment for anxiety and depression is warranted to alleviate the detrimental impact of these disorders on quality and of life and adverse events

Echocardiography overestimates LV mass in the elderly as compared to cardiac CT.

PURPOSE:Echocardiographic studies have shown an increase in LV mass with advanced age. However, autopsy and MRI studies demonstrate that with aging, LV mass is unchanged or slightly decreased, with a decrease in LV volume and an increase in wall thickness consistent with concentric remodeling. LV structural remodeling with aging may lead to an overestimation of LV mass in older adults when using standard echocardiography measurements and calculations. This study compared CT and echocardiographic LV mass calculation in younger and older patients and parameters associated with age-related LV remodeling. METHODS:Same subject modality comparison of echocardiographic and cardiac CT LV measurement with derivation of LV mass was performed retrospectively. Echocardiographic measurements were performed by a single observer in accordance with European Association of Cardiovascular Imaging (EACI)/American Society of Echocardiography (ASE) guidelines. CT measurements were performed in end-diastole on multiplanar reformatted image planes corresponding to those typically used in echocardiography. Calculated CT measurements were based on automatic segmentation of heart chambers via edge-tracing algorithms. RESULTS:129 patients were identified. In patients age 65 and older, LV mass was significantly higher when calculated using echocardiographic measurements compared to CT. Patients 65 years of age and older were found to have increased average wall thickness measurements with echocardiography but not with CT. The discrepancy between calculated echo and CT LV mass was reduced when using the mid-septal instead of proximal wall width for the EACI convention. CONCLUSION:In the elderly, increased echo-derived LV mass may reflect remodeling rather than a true increase in LV mass

Left Ventricular Mass and Geometry and the Risk of Ischemic Stroke

BACKGROUND AND PURPOSE: Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular events, but its effect on ischemic stroke risk is established mainly in whites. The effect of LV geometry on stroke risk has not been defined. The aim of the present study was to evaluate whether LVH and LV geometry are independently associated with increased ischemic stroke risk in a multiethnic population. METHODS: A population-based case-control study was conducted on 394 patients with first ischemic stroke and 413 age-, sex-, and race-ethnicity–matched community control subjects. LV mass was measured by transthoracic echocardiography. LV geometric patterns (normal, concentric remodeling, concentric or eccentric hypertrophy) were identified. Stroke risk associated with LVH and different LV geometric patterns was assessed by conditional logistic regression analysis in the overall group and age, sex, and race-ethnic strata, with adjustment for established stroke risk factors. RESULTS: Concentric hypertrophy carried the greatest stroke risk (adjusted odds ratio [OR], 3.5; 95% confidence interval [CI], 2.0 to 6.2), followed by eccentric hypertrophy (adjusted OR, 2.4; 95% CI, 2.0 to 4.3). Concentric remodeling carried slightly increased stroke risk (adjusted OR, 1.7; 95% CI, 1.0 to 2.9). Increased LV relative wall thickness was independently associated with stroke after adjustment for LV mass (OR, 1.6; 95% CI, 1.1 to 2.3). CONCLUSIONS: LVH and abnormal LV geometry are independently associated with increased stroke risk. LVH is strongly associated with ischemic stroke in all age, sex, and race-ethnic subgroups. Increased LV relative wall thickness imparts an increased stroke risk after adjustment for LV mass and is of additional value in stroke risk prediction

The Impact of COVID-19 Pandemic on Management and Outcome in Patients with Heart Failure

Background: The COVID-19 pandemic has adversely affected the provision of health care and disease management around the world. COVID-19 carries a high morbidity and mortality rate in elderly and people with comorbidities, including heart failure (HF). The present study addressed the clinical management and outcomes of HF patients during the pandemic. Methods: We evaluated the clinical management and survival rate of HF patients during the COVID-19 pandemic in Israel (March 2020–April 2021). Results: The cohort included 6748 patients with a diagnosis of HF during the study period. During this period, 843 HF patients (12.5%) were infected with COVID-19, and 194 died from COVID-19, a 23% mortality rate. Patients infected with COVID-19 had a higher percentage of diabetes and obesity. Predictors of mortality included age, male sex, reduced functional capacity, renal dysfunction, and absence of renin–angiotensin system inhibition. During the pandemic, there was a marked decrease in the usage of medical services in the cohort. Cardiovascular hospitalizations, all hospitalization, and emergency room visits were significantly decreased compared to the two years prior to the pandemic, particularly during the lockdowns. There was also an initial decrease in HF clinic visits. Mortality rates were very similar during the pandemic compared to previous years. There was a decline in non-COVID-19 deaths, which were replaced with deaths due to COVID-19. This may result from competing effects and reduced exposure to respiratory infections and other insults due to social distancing. Conclusions: Mortality rates in HF patients infected with COVID-19 were high. The COVID-19 pandemic resulted in the reduced usage of health services but without increased overall mortality

The Ratio of Hemoglobin to Red Cell Distribution Width: A Strong Predictor of Clinical Outcome in Patients with Heart Failure

Background: Hemoglobin (Hb) is a standard and widely available clinical parameter that predicts clinical outcomes in heart failure (HF) patients. Red cell distribution width (RDW) is also a routinely measured clinical parameter that is predictive of clinical outcomes in HF. The ratio between Hb and RDW has yet to be evaluated in HF. Methods: We evaluated the predictive value of the Hb/RDW ratio on clinical outcomes in patients with HF. All patients diagnosed with chronic HF at a health maintenance organization were evaluated for Hb/RDW ratio and followed for cardiac-related hospitalizations and death. Results: The study cohort included 6888 HF patients. The mean Hb/RDW ratio was 0.85 ± 0.18; median was 0.85 (interquartile range 0.72–0.98). Patients with a lower Hb/RDW ratio were more likely to be women and had more comorbidities. The overall two year-mortality rate was 23.2%. Decreasing quantiles of the Hb/RDW ratio were associated with reduced survival rates and reduced event-free survival from death or cardiovascular-hospitalizations. Multivariable Cox regression analysis after adjustment for significant predictors demonstrated that low Hb/RDW ratio was a significant predictor of mortality, with a graded increased risk as Hb/RDW ratio decreased. Lower Hb/RDW ratio was also a significant independent predictor of the combined endpoint of death or cardiovascular hospitalizations. A sensitivity analysis evaluating Hb/RDW ratio as a continuous parameter using restricted cubic splines demonstrated a continuous increase in the mortality risk with decreasing Hb/RDW ratio, p < 0.0001 for the linear model. Conclusions: Hb/RDW ratio is a significant prognostic tool for predicting HF mortality and cardiovascular hospitalizations

Hazard ratio for clinical outcome according to QRS-T angle levels by Cox regression analysis.

<p>Hazard ratio for clinical outcome according to QRS-T angle levels by Cox regression analysis.</p

DataSheet1_The effect of statins exposure during pregnancy on congenital anomalies and spontaneous abortions: A systematic review and meta-analysis.docx

Objective: To assess the effect of statin exposure during pregnancy on congenital anomalies and spontaneous abortions.Data sources: Electronic databases were searched from inception to January 2022.Study Eligibility Criteria: Cohort studies and randomized controlled trials (RCTs) evaluate the effect of treatment with statins on congenital anomalies in general and cardiac malformations in particular. Studies evaluating spontaneous abortions were included as a secondary outcome.Study appraisal and synthesis methods: Pooled odds ratio was calculated using a random-effects model and meta-regression was utilized when applicable.Results: Twelve cohort studies and RCTs were included in the analysis. Pregnancy outcomes of 2,447 women that received statins during pregnancy were compared to 897,280 pregnant women who did not. Treatment with statins was not associated with a higher risk of overall congenital anomalies (Odd Ratio = 1.1, CI (0.9–1.3), p = 0.33, I2 = 0%). Yet, cardiac malformations were more prevalent among neonates born to statins users (OR = 1.4, CI (1.1–1.8), p = 0.02, I2 = 0%). The risk was higher when exposure occurred during the first trimester. This finding was statistically significant in cohort studies, but not in RCTs. Statin treatment was also associated with a higher rate of spontaneous abortions (OR = 1.5, CI (1.1–2.0), p = 0.005, I2 = 0%). In meta-regression analysis, no significant association between lipophilic statins and the rate of congenital anomalies was found.Conclusion: Overall, treatment with statins during pregnancy was not associated with an increased risk of congenital anomalies. A slight risk elevation for cardiac malformation and spontaneous abortions was seen in cohort studies but not in RCTs.Systematic Review Registration:clinicaltrials.gov, identifier [CRD42020165804 17/2/2020]The meta-analysis was presented online at 42nd annual meeting of SMFM. January 31-5 February 2022.</p